It has been widely accepted that carcinogenesis is a multistep process involving genetic and epigenetic changes that dysregulate molecular control of cell proliferation and differentiation. The genetic changes can include activation of proto-oncogenes and/or the inactivation of tumor suppressor genes that can initiate tumorigenesis as well as lead to the progression of tumors. For example, the tumor suppressor gene p53 may be involved in late stages of colorectal carcinomas (Baker, S. J. et al., (1989) Science, 244: 217-221) and a putative metastasis suppressor gene, nm23, was found down-regulated in metastatic tumors versus nonmetastatic tumors (Steeg, P. S. et al., (1988) J. Natl. Canc. Inst., 80:200-204). In addition, the activation of ras oncogene and the amplification of N-myc have been associated with progression of human tumors such as breast carcinomas (Liu, E. et al., (1988) Oncogene 3:323-327); and neuroblastomas (Brodeur, G. M. et al., (1984) Science, 224:1121-1124; Schwab, M. et al., (1984) Proc. Natl. Acad. Sci. U.S.A., 81:4940-4944) but they are unlikely to be universal determinants of tumor progression (Nicolson, G. L. Bio Essays, 13:337-342 (1991).
However despite these advances in understanding the genetic changes underlying carcinogenesis, metastasis, which is the main cause of death for most cancer patients (Rosenberg, S. A., Surgical Treatment of Metastasis Cancer (Lippincott, Philadelphia Pa. 1987)), remains one of the most important but least understood aspects of cancer (Liotta, L. A. et al. (1991) Cell, 64:327-336; Nicolson, G. L. (1991) BioEssays, 13:337-342 and Steeg, P. S. (1992) Curr. Opin. Oncol., 4:134-141). Accordingly, the isolation of metastasis tumor suppressor genes is of great importance for the diagnosis and therapy of cancers.
Cell fusion studies by Ramshaw et al. ((1983) Int. J. Cancer, 32:471-478) in which hybridization of non-metastatic and metastatic tumor cells produced cell hybrids which are tumorigenic but no longer metastatic demonstrated the existence of metastasis suppressor genes. More recently, Ichikawa et al. (1991) Cancer Res., 51:3788-3792) demonstrated that the metastatic ability of rat prostatic cancer cells was suppressed when fused to non-metastatic cancer cells and that the reexpression of metastasis was associated with the consistent loss of a normal rat chromosome. A subsequent study using micro-cell-mediated chromosome transfer further mapped a putative human metastasis suppressor gene to the 11p11.2-13 region of human chromosome 11. (Ichikawa et al. (1992) Cancer Res., 52:3486-3490) In this study, these researchers demonstrated that a hybrid retaining human chromosome 11cent-p13 showed a suppression of metastasis while hybrids retaining 11cent-p11.2 did not.
In sum, the data presented in the Ichikawa et al. papers suggested that a putative suppressor gene in the p11.2-13 region of human chromosome 11 may play a role in metastasis. However to date, no gene has been identified in this region which is a candidate metastasis suppressor gene. Thus, there is a need in the art to identify such gene(s) in this chromosome region and to determine if any such gene(s) is associated with metastasis.